A central scientific question of this proposal's is finding additional evidence for the role of STING, a typical innate immune sensor of cytosolic DNA, in activation program in T cells. While studying STING in typical innate environment (macrophages), we identified via search of public database high levels of STING mRNA in lymphoid tissues, which prompted us to set up further experiments, in which we used the synthetic STING- agonist DMXAA to observe direct activation of T cells resulting in production of type I IFN followed by significant upregulation of multiple interferon stimulated genes (ISG). We next set up studies that led us to discoveries with paradigm-shifting potential. First, we detected production of type I interferon by DMXAA-activated T cells which is accompanied by activation of hundreds of ISGs. This activation program is supported by evidence showing that transcriptional activator IRF3 and TBK1 kinase is activated downstream of STING. Second, we identify ligand-independent effects of the loss of STING in T cells. Because of widespread (20%) of loss-of-function allele of STING is linked to several pathologies in humans, possible effect of the mutant allele on T cells has to be considered. Our subsequent discovery that T cells can produce type I IFNs, TNF, and other inflammatory cytokines in response to STING activation may have important implications for many therapies, including cancer treatments: DMXAA was initially tested as a cancer drug because of its anti-tumor and anti-vascularization effects; DMXAA was also reported to stimulate both innate and adaptive immune responses but the mechanism was unknown. Our data show that genetic ablation of STING severely attenuates the ability of T cells to proliferate upon TCR-ligation. Interestingly, activation of STING with DMXAA also inhibits TCR-induced proliferation. These two observations lead us to a new model that has STING promote TCR signaling, possibly via interaction with one of the downstream components, but undergoing translocation away from TCR following recognition of DMXAA. Thus DMXAA becomes a tool for tweaking TCR-activation in T cells. Although this has to be further supported, the value of this hypothesis is highly novel because it will change the way we perceive T cells. We have designed experiments, which may provide support for this hypothesis. In experimental settings, further evidence could be obtained by using in vitro lentiviral or HIV infection.